Form Of X-linked Mental Retardation Research Articles

Tetraspanin 7 and its closest paralog tetraspanin 6: membrane organizers with key functions in brain development, viral infection, innate immunity, diabetes and cancer.

Tetraspanin (TSPAN) protein family forms a family of transmembrane proteins that act as organizers/scaffold for other proteins. TSPANs are primarily present on plasma membranes although they are also found in other biological membranes. They are organized in tetraspanin-enriched microdomains (TEMs), which allow spatiotemporal tuning of protein functions through the control of their membrane localization. TSPAN6 and TSPAN7 are close paralogs expressed in different tissues, TSPAN7 being highly expressed in the brain. Their functions only started to be unveiled in the late 2000's and are still poorly understood. Here, we introduce how TSPAN7 was first highlighted has a protein mutated in some forms of X-linked mental retardation, which waslater proposed to be caused by defects in neuronal morphogenesis and synaptic transmission. We then discuss the impacts TSPAN7 has on cell morphology of dendritic cells and osteoclasts, through rearrangement of actin cytoskeleton and how TSPAN7 was shown to be a target of autoantibody in patients suffering from type 1 diabetes. Finally, we are addressing the double edge sword that is TSPAN7 in cancer. In the second part of this review, we address the known roles of TSPAN6 and how this protein was shown to participate in synaptic transmission and in amyloid precursor protein secretion, which may contribute to Alzheimer's disease pathology. We conclude this review by discussing the anti-inflammatory effect of TSPAN6.

Generation of an iPSC line (SDQLCHi015-A) from peripheral blood mononuclear cells of a patient with mental retardation type 15 carrying c.1007_1011del, p.(Ile336fs) in CUL4B gene.

CUL4B gene mutation can cause intelligence deficiency 15, a syndromic form of X-linked mental retardation characterized by severe intellectual deficit associated with short stature, craniofacial dysmorphism, speech delay and impairment, tremor and gait ataxia. Here, we generated iPSCs from a Chinese patient with c.1007_1011del (p.(Ile336fs)) in CUL4B gene by reprogramming peripheral blood mononuclear cells with non-integrating vectors. The generated iPSC line (SDQLCHi015-A) expresses pluripotency markers, presents a normal karyotype and is able to differentiate into three germ layers.

Molecular screening of xq27.3 chromosomal region and cytogenetic abnormalities of fragile-x syndrome in mental retardation peoples of tamil nadu, south india

Objective Fragile X syndrome is the most common inherited form of X-linked mental retardation. The aim of this study was to screen and identify fragile X syndrome-affected individuals in Tamil Nadu (South India) using DNA-based molecular analysis and chromosomal abnormalities. Materials and Methods Genomic DNA extracted from 47 (29 males and 18 females) individuals with mental retardation, including 47 controls, was analyzed using polymerase chain reaction, DNA gel electrophoresis and sequence analysis. Individuals with mutation were determined according to the CGG repeat size in the FMR1gene on chromosome Xq27.3. At same set of mentally retarded individuals, including controls 3ml of blood were collected in Lithium heparin tubes. The blood samples were incubated in 72 hours under culture conditions and harvested for Gbanding technique and results were guaranteed by SKY techniques. Results The sequence analysis shows that the CGG repeat was found in fragile x site which expressed Fragile X syndrome highly when compared to healthy controls. The major Chromosomal aberrations (CA) like deletion, translocation and mosaic were also found. However, when compare with experimental subjects, the controls exhibited low levels of CA (P Conclusion Results of this investigation suggest that, deregulation of the FMR1 gene might have responsible for fragile X syndrome of mental retardation, and CA among the individuals. Further investigation of this study helps to predicts the causes of this syndrome in molecular level (RNA based FMR1gene – Protein).

Molecular studies on ARX gene in syndromic and non-syndromic mental retardation

Background Mental retardation (MR) is frequently the result of genetic mutations. Syndromic mental retardation is intellectual deficits associated with other medical and behavioral signs and symptoms. Non-syndromic mental retardation refers to intellectual deficits that appear without other abnormalities. The newly identified ARX (Aristaless related homeobox) gene consists of five exons and encodes 562 amino acid proteins and is thought to regulate brain development. Mutations in the ARX gene are associated with a diverse spectrum of phenotypes ranging from severe developmental abnormalities of the brain to syndromic and nonsyndromic forms of X-linked mental retardation (XLMR) syndromes that can be associated with normal or abnormal brain morphology. Mutations in the human ARX gene are the major cause of developmental and neurological disorders.

Calcium Regulatory Protein, Regucalcin, may be a Key Molecule in Brain Disease

Regucalcin was discovered in 1978 as a novel calcium-binding protein [1-4]. Regucalcin (RGN) and its gene (rgn) are identified in over 15 species of vertebrate and invertebrates consisting of regucalcin family [5]. Regucalcin plays a multifunctional role in cell regulation; maintaining of intracellular calcium (Ca2+) homeostasis, suppressions of cell signaling, protein synthesis, nuclear deoxyribonucleic acid and ribonucleic acid synthesis and cell proliferation and apoptosis, and regulation of gene expression in various tissue and cell types [6,7]. Regucalcin has been proposed to play a pivotal role as a suppressor protein in signaling systems in maintaining of cell homeostasis [7]. The regucalcin gene is located on the X chromosome [8,9]. Interestingly, the map location for a growing number of diseases with a genetic basis is encompassed in human X chromosome, and these are known to include syndromic and non-syndromic forms of X-linked mental retardation and X-linked neuromuscler diseases [9]. Regucalcin is expressed in rat brain neuron, and it is decreased in the cerebral cortex and hippocampus of brain with aging [10,11]. There is growing evidence that regucalcin plays a pivotal role in brain neuronal cell regulation.

Christianson syndrome in a patient with an interstitial Xq26.3 deletion

Interstitial deletions of chromosome band Xq26.3 are rare. We report on a 2-year-old boy in whom array comparative genomic hybridization analysis revealed an interstitial 314 kb deletion in Xq26.3 affecting SLC9A6 and FHL1. Mutations in SLC9A6 are associated with Christianson syndrome (OMIM 300243), a syndromic form of X-linked mental retardation (XLMR) characterized by microcephaly, severe global developmental delay, ataxia and seizures. FHL1 mutations cause Emery-Dreifuss muscular dystrophy (OMIM 310300), X-linked myopathy with postural muscle atrophy (XMPMA, OMIM 300696), scapuloperoneal myopathy (OMIM 300695), or reducing body myopathy (OMIM 300717, 300718). The clinical problems of the patient reported here comprised severe intellectual disability, absent speech, ataxia, epilepsy, and gastroesophageal reflux, and could mostly be attributed to SLC9A6 insufficiency. In contrast to the majority of reported Christianson syndrome patients who were microcephalic, this patient was normocephalic, but his head circumference had decelerated from the 50th centile at birth to the 25th centile at the age of 2 ²/¹² years. Muscle problems due to the FHL1 deletion are not to be expected before late childhood, which is the earliest age of onset for FHL1 associated Emery-Dreifuss muscular dystrophy. This patient broadens the spectrum of SLC9A6 mutations and contributes to the clinical delineation of Christianson syndrome. This is also the first patient with a deletion affecting both SLC9A6 and the complete FHL1 gene.

Homophilic Adhesion Mechanism of Neurofascin, a Member of the L1 Family of Neural Cell Adhesion Molecules

The L1 family neural cell adhesion molecules play key roles in specifying the formation and remodeling of the neural network, but their homophilic interaction that mediates adhesion is not well understood. We report two crystal structures of a dimeric form of the headpiece of neurofascin, an L1 family member. The four N-terminal Ig-like domains of neurofascin form a horseshoe shape, akin to several other immunoglobulin superfamily cell adhesion molecules such as hemolin, axonin, and Dscam. The neurofascin dimer, captured in two crystal forms with independent packing patterns, reveals a pair of horseshoes in trans-synaptic adhesion mode. The adhesion interaction is mediated mostly by the second Ig-like domain, which features an intermolecular β-sheet formed by the joining of two individual GFC β-sheets and a large but loosely packed hydrophobic cluster. Mutagenesis combined with gel filtration assays suggested that the side chain hydrogen bonds at the intermolecular β-sheet are essential for the homophilic interaction and that the residues at the hydrophobic cluster play supplementary roles. Our structures reveal a conserved homophilic adhesion mode for the L1 family and also shed light on how the pathological mutations of L1 affect its structure and function.

The Coffin-Lowry Syndrome-Associated Protein rsk2 and Neurosecretion

Coffin-Lowry syndrome (CLS) is a syndromic form of X-linked mental retardation, characterized in male patients by psychomotor and growth retardation and various skeletal anomalies. CLS is caused by mutations in the RPS6KA3 gene, which encodes RSK2, a growth factor-regulated protein kinase. Cognitive deficiencies in CLS patients are prominent, but markedly variable in severity, even between siblings. However, the vast majority of patients are severely affected, with mental retardation ranging from moderate to profound. We used a RSK2-KO mouse model that shows no obvious brain abnormalities at the anatomical and histological levels to study the function of RSK2 in neurosecretion. Behavioral studies revealed normal motor coordination, but a profound retardation in spatial learning and a deficit in long-term spatial memory, providing evidence that RSK2 plays similar roles in mental functioning both in mice and human. We found that associative LTP at cortical inputs to the lateral amygdala was blocked in Rsk2 KO mice. Using an RNA interference rescue strategy in PC12 cells, we were able to demonstrate that RSK2 regulates catecholamine release through the phosphorylation of PLD. These results provide the first molecular evidence that RSK2 could regulate neurotransmitter release by activating PLD production of lipids required for exocytosis.

Adaptin' endosomes for synaptic vesicle recycling, learning and memory

Adaptin' endosomes for synaptic vesicle recycling, learning and memory

A novel nonsense mutation in CUL4B gene in three brothers with X‐linked mental retardation syndrome

Cabezas syndrome (MIM 300354) is a recently identified syndromic form of X-linked mental retardation (XLMR) caused by mutations in the CUL4B gene. In total, nine XLMR families carrying mutations in the CUL4B gene have been described to date. Here, we present a detailed clinical phenotype of three affected brothers of Polish descent. Based on the symptoms, we made a clinical diagnosis of Cabezas syndrome, which was subsequently confirmed by identification of a novel nonsense mutation (c.2107A-->T, p.703K-->X) in exon 18 of the CUL4B gene. The mutation was inherited from an asymptomatic mother and was present in all three affected brothers. The patients presented with typical features of Cabezas syndrome, such as severe mental retardation, speech impairment, hyperactivity, seizures, intention tremor, inguinal hernia, small feet, and craniofacial dysmorphism. In addition to previously described symptoms, syndactyly of the second and third toes and skin manifestations (hyperhydrosis and keratosis pilaris) were present in our cases. Our report provides further support that Cabezas syndrome is a recognizable syndromic form of XLMR. We conclude that the CUL4B gene should be screened in males with severe speech impairment and primary intention tremor, especially if characteristic facial dysmorphism is also present.

The aristaless Arx gene one gene for many interneuronopathies

The ARX (Aristaless-related (X-linked) homeobox) gene is not only present in arthropods and their ancestors, but also in vertebrates including humans (ARX orthologs). The gene is composed of 5 coding exons and it is expressed predominantly in foetal and adult brain and skeletal muscle. In this review we report on our experience and review the existing literature on the genotype and phenotype heterogeneity associated with ARX abnormalities in humans ranging from severe neuronal migration defects (e.g., lissencephaly), to mild forms of X-linked mental retardation without apparent brain abnormalities. The ARX-related disorders are reviewed focusing on their clinical features and on the role of the ARX gene. It has yet to be established whether the molecular defect alone could cause a given cerebral abnormality and/or malformation or an additional or related molecular or environmental event could contribute to a given phenotype in molecularly.

Coffin–Lowry syndrome

Coffin-Lowry syndrome (CLS) is a syndromic form of X-linked mental retardation, which is characterized in male patients by psychomotor and growth retardation and various skeletal anomalies. Typical facial changes and specific clinical and radiological signs in the hand are useful aids in the diagnosis. CLS is caused by mutations in the RPS6KA3 gene located at Xp22.2, which encodes RSK2, a growth-factor-regulated protein kinase. RPS6KA3 mutations are extremely heterogeneous and lead to loss of phosphotransferase activity in the RSK2 kinase, most often because of premature termination of translation.

Long time no see: the Type and Contre-type concept

Long time no see: the Type and Contre-type concept

Immunohistochemical localisation of the creatine transporter in the rat brain

Creatine (Cr) is required to maintain ATP levels in the brain. The transport of Cr across the blood–brain barrier and into neurones requires a specific creatine transporter (CRT). Mutations in the CRT gene ( SLC6A8) result in a novel form of X-linked mental retardation, characterised by developmental delays, seizures and a complete absence of Cr from the brain. To identify cell types and regions that depend on Cr for energy metabolism we have determined the regional and cellular localisation of CRT protein in the rat brain using immunohistochemical techniques with a highly specific, affinity-purified, CRT antibody. The results show high levels of CRT localisation is associated with specific brain regions and certain cell types. The CRT is predominantly found in neurones. CRT immunoreactivity is particularly abundant in the olfactory bulb, granule cells of the dentate gyrus of the hippocampus, pyramidal neurones of the cerebral cortex, Purkinje cells of the cerebellum, motor and sensory cranial nerve nuclei in the brainstem and the dorsal and ventral horns of the spinal cord. Low levels of CRT were seen in the basal ganglia and white matter. Overall, CRT was found to show high intensities of labelling in the major motor and sensory regions of the forebrain, brainstem and spinal cord and forebrain regions associated with learning, memory and limbic functions. It is hypothesised that regions with high CRT expression are likely to have high metabolic ATP requirements and that areas with low CRT levels are those regions which are particularly vulnerable in neurodegenerative diseases.

Molecular Recognition of the Palmitoylation Substrate Vac8 by Its Palmitoyltransferase Pfa3

Palmitoylation of the yeast vacuolar protein Vac8 is important for its role in membrane-mediated events such as vacuole fusion. It has been established both in vivo and in vitro that Vac8 is palmitoylated by the Asp-His-His-Cys (DHHC) protein Pfa3. However, the determinants of Vac8 critical for recognition by Pfa3 have yet to be elucidated. This is of particular importance because of the lack of a consensus sequence for palmitoylation. Here we show that Pfa3 was capable of palmitoylating each of the three N-terminal cysteines of Vac8 and that this reaction was most efficient when Vac8 is N-myristoylated. Additionally, when we analyzed the Src homology 4 (SH4) domain of Vac8 independent of the rest of the protein, palmitoylation by Pfa3 still occurred. However, the specificity of palmitoylation seen for the full-length protein was lost, and the SH4 domain was palmitoylated by all five of the yeast DHHC proteins tested. These data suggested that a region of the protein C-terminal to the SH4 domain was important for conferring specificity of palmitoylation. This was confirmed by use of a chimeric protein in which the SH4 domain of Vac8 was swapped for that of Meh1, another palmitoylated and N-myristoylated protein in yeast. In this case we saw specificity mimic that of wild type Vac8. Competition experiments revealed that the 11th armadillo repeat of Vac8 is an important element for recognition by Pfa3. This demonstrates that regions distant from the palmitoylated cysteines are important for recognition by DHHC proteins.

The impact of spermine synthase (SMS) mutations on brain morphology

Snyder-Robinson syndrome (SRS) is a form of X-linked mental retardation resulting from mutations in spermine synthase (SMS), which impact neurodevelopment and cognitive outcome. We obtained cerebral, cerebellum, hippocampus, and red nucleus volumes from two males with SRS and 24 age- and gender-matched typically developing controls using volumetric neuroimaging analyses. Total brain volume was enlarged in males with SRS while cerebellum, hippocampus, and red nucleus volumes tended to be reduced compared to controls. Mutations of the X chromosome may modulate the risk for mental retardation through altered early neurodevelopment, disruption in receptor function, and ongoing neural organization and plasticity. Disruption of SMS function may negatively affect regional brain volumes that subserve cognitive and motor abilities. This research provides valuable insight into the effects of polyamine function on brain development.

Partial reversal of Rett Syndrome-like symptoms in MeCP2 mutant mice

Rett Syndrome (RTT) is a severe form of X-linked mental retardation caused by mutations in the gene coding for methyl CpG-binding protein 2 (MECP2). Mice deficient in MeCP2 have a range of physiological and neurological abnormalities that mimic the human syndrome. Here we show that systemic treatment of MeCP2 mutant mice with an active peptide fragment of Insulin-like Growth Factor 1 (IGF-1) extends the life span of the mice, improves locomotor function, ameliorates breathing patterns, and reduces irregularity in heart rate. In addition, treatment with IGF-1 peptide increases brain weight of the mutant mice. Multiple measurements support the hypothesis that RTT results from a deficit in synaptic maturation in the brain: MeCP2 mutant mice have sparse dendritic spines and reduced PSD-95 in motor cortex pyramidal neurons, reduced synaptic amplitude in the same neurons, and protracted cortical plasticity in vivo. Treatment with IGF-1 peptide partially restores spine density and synaptic amplitude, increases PSD-95, and stabilizes cortical plasticity to wild-type levels. Our results thus strongly suggest IGF-1 as a candidate for pharmacological treatment of RTT and potentially of other CNS disorders caused by delayed synapse maturation.

Molecular Screening of Fragile X Syndrome in Children with Mental Retardation in Hualien

Objective Fragile X syndrome is the most common inherited form of X-linked mental retardation (XLMR). The aim of this study was to screen for and identify fragile X syndrome-affected individuals using DNA-based molecular approaches at a special education school for the mentally retarded in Hualien, Taiwan. Materials and Methods Genomic DNA extracted from 217 individuals with mental retardation, including 148 males and 69 females, was analyzed using polymerase chain reaction, DNA gel electrophoresis and Southern blot analysis. Individuals with the full mutation or premutation were determined according to the CGG repeat size in the 5′-untranslated region in the FMR1 gene on chromosome Xq27.3. Results A total of 217 individuals with mental retardation were screened, and three (1.38%) were identified as having fragile X full mutation. Two of the 148 males (1.35%) and one of the 69 females (1.44%) had this mutation. The incidence is very close to that in previous reports in Western Taiwan. Female carriers of fragile X syndrome were not found in this study. Conclusion We established a molecular screening approach and report the incidence of fragile X syndrome in a mentally retarded population in Eastern Taiwan. The molecular study and genetic counseling for other family members will continue in the future.

Dopaminergic system dysregulation in the mrsk2_KO mouse, an animal model of the Coffin‐Lowry syndrome

The Coffin-Lowry syndrome, a rare syndromic form of X-linked mental retardation, is caused by loss-of-function mutations in the hRSK2 (RPS6KA3) gene. To further investigate RSK2 (90-kDa ribosomal S6 kinase) implication in cognitive processes, a mrsk2_KO mouse has previously been generated as an animal model of Coffin-Lowry syndrome. The aim of the present study was to identify possible neurochemical dysregulation associated with the behavioral and morphological abnormalities exhibited by mrsk2_KO mice. A cortical dopamine level increase was found in mrsk2_KO mice that was accompanied by an over-expression of dopamine receptor of type 2 and the dopamine transporter. We also detected an increase of total and phosphorylated extracellular regulated kinase that may be responsible for the increased level of tyrosine hydroxylase phosphorylation also observed. By taking into consideration previously reported data, our results strongly suggest that the dopaminergic dysregulation in mrsk2_KO mice may be caused, at least in part, by tyrosine hydroxylase hyperactivity. This cortical hyperdopaminergia may explain some non-cognitive but also cognitive alterations exhibited by mrsk2_KO mice.

Simultaneous expression of the rare and common fragile sites on the X chromosome

The fragile X [fra(X)] syndrome is the most common inherited form of X-linked mental retardation and is associated with a rare folate sensitive fragile site on the X chromosome at band Xq27.3. Recently, a common fragile site located at chromosome band Xq27.2 was delineated (Sutherland & Baker 1990). In order to confirm the previous findings and to further investigate the conditions required for induction of both types of fragile sites, we studied the use of four experimental protocols. Samples from a control male, two fra(X) males and a fra(X) carrier female were studied. Both common and rare fragile sites were seen in the samples from the fra(X) subjects. Up to 4% of cells showed both common and rare fragile sites on the same X chromosome at the 500 band level. The rare and common fragile sites on the X chromosome could be clearly distinguished. From 1 to 3% of the control cells exhibited the common fragile site, while none exhibited the rare fragile site. These protocols should be useful in resolving questionable fra(X) syndrome diagnoses.